This application addresses broad Challenge Area (08) Genomics, and specific Challenge Topic 08-CA-101* Augmenting Genome-Wide Association Studies. The development of glioblastoma (GBM) has been hypothesized to be associated with relatively common germline alterations with limited penetrance. Collaborating with the group at the University of California at San Francisco (UCSF) we recently reported that SNPs mapping to 9p and 20q are associated with the development of GBM. We propose to characterize the germline alterations within these 9p and 20q regions and to correlate these with glioma 9p deletion and 20q gain. Specific Aim 1: Perform detailed germline genetic analysis of the associated 9p and 20q regions using 1200 cases and controls to determine the prevalence of known polymorphisms and new alterations. Aim 1a: Perform custom genotyping of 600 previously genotyped cases and matched controls for all non-redundant SNPs to better define haplotypes. Impute haploytpes and evaluate their association with GBM development. Aim 1b: Perform high-throughput sequencing of the ~200kb and ~100kb regions within 9p and 20, respectively, in 50 GBM cases and 50 controls that carry the imputed at-risk haplotypes. To directly determine haplotype structure, perform high-through-put sequencing of 50 isolated at-risk and non-risk chromosomes. Aim 1c: Custom genotype candidate polymorphisms in 600 new cases and matched controls to validate new alterations from Aims 1a and 1b. Aim 1d: Perform custom aCGH analysis of the 9p and 20q regions to ascertain copy number variants. Specific Aim 2: Perform detailed genetic analysis and expression analysis of gliomas from the cases. Aim 2a: Using FISH and custom CGHa define glioma 9p deletion and 20q gain status. Aim 2b: Sequence all exons in the 9p and 20q regions. Assess methylation of target gene promoters. Aim 2c: Evaluate the tumor expression of all known exons and miRNAs within the targeted regions. Determine the underlying GBM genetic subtype. Specific Aim 3: Correlate polymorphism/ alteration/haplotype prevalence differences and with acquired glioma alterations to generate a list of candidate germline 9p and 20q mutations likely to be associated with the development of gliomas. Gliomas cause significant morbidity and mortality. Approximately 18,500 people in the U.S. are diagnosed with glioma each year. Because most gliomas are biologically aggressive, approximately 12,800 people in the U.S. succumb to these tumors every year. Understanding the predisposition to gliomas will have major implications for the prevention of gliomas as well as the management of these tumors.